The thyrotropin response to thyrotropin-releasing hormone in endogenous depression

The maximal response of thyrotropin (TSH) to thyrotropin-releasing hormone (TRH) (Δ max TSH) is reduced in endogenous depression (ED). In the majority of studies Δ max TSH was reduced to the same degree in unipolar and bipolar depression, as well as in manic patients. Decreases present in anorexia nervosa and heroin addiction possibly were secondary to reduced caloric intake and administration of heroin, respectively. When the TRH test was repeated in patients with ED who were clinically cured after short-term antidepressant therapy, the patients could be divided into two groups, one with an increase of Δ max TSH > 2.0 μU/ml, and another with an increase <-2.0 μU/ml. After withdrawal of treatment, patients in the former group did well for at least six months, whereas patients in the latter group relapsed within a median time of two months. Predictions were correct in 60 of 66 patients. However, the change of the TSH response during the course of ED is relatively small, and thus great care should be taken to diminish both the analytical and the normal biological variations. Electroconvulsive therapy (ECT), tricyclic antidepressants, tryptophan and sleep deprivation, respectively, did not influence Δ max TSH, whereas lithium, because of an inhibition of thyroid hormone release and negative feedback, induced an increase of Δ max TSH unrelated to the course of ED. p] Although serum levels of the thyroid hormones and cortisol changed during the course of ED, no relationship could be demonstrated between Δ max TSH on the one hand and the free serum levels of thyroxine and 3,3′,5-triiodothyronine, as expressed by the free indices, or the serum levels of cortisol, on the other hand. Neither did Δ max TSH in the depressed patients correlate significantly with the cerebrospinal fluid (CSF) levels of thyroxine, cortisol or TRH. Thus, CSF levels of TRH were unrelated to the clinical outcome of ED, but 70% of the values exceeded the upper range of neurologic controls. Therefore, it is possible that CSF TRH might be of diagnostic value in patients with ED.     

The thyrotropin response to thyrotropin-releasing hormone as a predictor of response to treatment in depressed outpatients.

We evaluated the predictive value of the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in 32 depressed outpatients completing a double-blind placebo-controlled trial of s-adenosyl-l-methionine (SAMe), which failed to show any significant difference between SAMe and placebo. Treatment response was defined as the change in Hamilton Rating Scale for Depression (HRSD-24) score between baseline and the end of the six-week trial. Subjects with TSH response outside the normal range (7-25 uU/ml) had a significantly greater response than patients with a normal response. There was also a significant correlation between absolute deviations from the mean TSH response (16 uU/ml) and changes in HRSD-24 scores.     

The effects of carbamazepine on the thyrotropin response to thyrotropin-releasing hormone

A thyrotropin (thyroid-stimulating hormone; TSH) stimulation test with thyroid-releasing hormone (TRH) was performed on six patients with a DSM-III diagnosis of major depressive disorder, both before and during a trial of carbamazepine. Carbamazepine, an anticonvulsant effective in the treatment of affective illness, caused a reduction in the TSH response to TRH. This finding suggests that carbamazepine may decrease thyroid function primarily at the level of the pituitary in affectively ill patients.     

Prolactin and growth hormone response to levodopa in affective illness

Prolactin (PRL) and growth hormone (GH) response to L-Dopa have been studied in 51 affectively ill women (26 unipolar and 25 bipolar) before and after amitriptyline treatment and in 14 normal female controls. There was no difference in GH response to L-dopa in all groups studied except for bipolar postmenopausal women, who showed a blunted GH response to L-Dopa compared to bipolar premenopausal women. After amitriptyline treatment, no difference in GH response was found in all groups studied. Basal PRL levels were significantly lower in unipolar premenopausal and bipolar premenopausal patients in comparison to their controls. PRL response to L-Dopa was significantly less inhibited in postmenopausal controls than in premenopausal controls and in bipolar premenopausal patients compared to premenopausal controls. These data provide further evidence of hypothalamo-pituitary dysfunction in subgroups of affective disorders and emphasize the importance of considering the menopausal status in neuroendocrine studies of psychiatric disorders.     

Effect of amitriptyline on the thyrotropin response to thyrotropin-releasing hormone in endogenous depression

Patients with endogenous depression whose depressive episodes were clinically resolved after electroconvulsive therapy were divided into two groups: one in which patients remained well (n = 16) and another in which patients relapsed within 6 months (n = 11). Treatment with amitriptyline for 3 weeks did not affect the median thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropin-releasing hormone (TRH) in recovered patients, whereas that in relapsed patients was significantly enhanced. The data suggest that amitriptyline affects the TSH response to TRH differently in stably recovered and relapsed patients. If this effect is maintained beyond the 3-week period studied, treatment with amitriptyline will invalidate the predictive value of the TRH test.     

Neuroendocrine and amine studies in affective illness.

(1) There are limitations to some of these studies because of the small number of patients involved, but our data suggest that maximal Growth Hormone (GH) levels after induced hypoglycemia were lower in depressed patients than in control subjects. (2) Manic patients showed low GH peaks during the Insulin Tolerance Test (ITT), and furthermore urinary 3-methoxy-4-hydroxyphenylene glycol (MHPG) excretion rates in mania were indistinguishable from normals but higher than in depressed patients. (3) The apomorphine-induced GH response was essentially normal in affective disorder patients, while acute schizophrenic patients showed hypersensitivity of postsynaptic dopamine receptors. (4) Confirming previous studies by Maas et al. (1968, 1972), patients with depressive illness were found to have signicantly lower urinary MHPG excretion, whereas borderline patients with depressive symptomatology had MHPG values similar to control subjects.     

Biogenic amine metabolites in cerebrospinal fluid of patients with affective disorders

Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in lumbar CSF from 33 patients with affective illnes and from 23 neurological controls. The group of patients with affective illness comprised 29 depressed and four manic patients. During illness, the concentration of HVA was higher in the depressed patients (P >0.001) than in the controls. Both unipolar and bipolar depressed patients had increased HVA levels (P >0.001 and P >0.05, respectively). The concentration of MHPG was greater than control values in the unipolar (P < 0.001) and bipolar (P < 0.002) subgroups but did not differ from control values in the depressed group as a whole. The concentration of 5-HIAA in the depressed patients as a whole and in the unipolar and bipolar subgroups did not differ from control concentrations. During illness the manic patients had increased levels of HVA (P >0.01) and normal levels of 5-HIAA and MHPG. Sixteen of the 29 depressed patients had a second lumbar puncture after they had recovered. Compared with the pre-recovery values, the concentration of HVA was reduced in the unipolar depressives (P < 0.01) and the concentration of 5-HIAA lowered in the depressed group as a whole (P >0.02). The present findings suggest involvement of catecholamines in affective disorders.     

Effects of age and diagnosis on thyrotropin response to thyrotropin-releasing hormone in psychiatric patients

The thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropin-releasing hormone (TRH) was studied in 64 age-matched healthy volunteers, 44 patients with endogenous depression, and 21 patients with schizophrenia. A significant negative correlation between delta TSH and age was found both in healthy subjects and in depressed patients. We based our comparison on normal ranges for delta TSH calculated from the delta TSH values in the healthy subjects related to age. It was then seen that blunted TSH response to TRH does not occur significantly more often in depression (13.6%) than in healthy controls (4.7%). Blunted TRH test results were also found in a considerable number of severely ill schizophrenic patients (19%). Application of an improved radioimmunoassay revealed a highly significant correlation between TSH values at baseline and after stimulation, and showed decreased baseline TSH levels in subjects with blunted TRH test results.     

Pirenzepine inhibits growth hormone, but not thyrotropin response to thyrotropin-releasing hormone in patients with endogenous depression

In order to evaluate whether in endogenous depression the anomalous growth hormone (GH) response to thyrotropin-releasing hormone (TRH) is mediated by muscarinic cholinergic receptors, 12 patients were tested with TRH (200 micrograms iv) with and without previous treatment with the muscarinic cholinergic receptor blocker pirenzepine (40 mg iv 10 min before TRH). Control tests with normal saline also were performed. Administration of normal saline did not alter serum GH levels. In contrast, TRH injections significantly increased serum GH concentrations by about three-fold. This response was inhibited by pretreatment with pirenzepine. Another neuroendocrine marker of endogenous depression, the low TSH increase in response to TRH (delta less than or equal to 7 microU/ml), was observed in our patients. Pretreatment with pirenzepine did not modify this response. These data indicate that in patients with endogenous depression a muscarinic cholinergic mechanism is involved in the GH response but not in the TSH response to TRH.     

Administration of thyrotropin-releasing hormone at weekly intervals results in a diminished thyrotropin response

A diminished thyrotropin (TSH) response to the administration of thyrotropin-releasing hormone (TRH) has been widely reported in depressed patients. Repeated TRH administration at short intervals has been shown to produce a diminished TRH response in healthy subjects. In the present study, TRH (400 micrograms) was administered to ten healthy male subjects at weekly intervals for 4 weeks. The TSH response to TRH diminished steadily from 8.2 +/- 1.3 microU/ml on Trial 1 to 6.3 +/- 0.7 microU/ml on Trial 4 (p less than 0.05). No change in the prolactin response to TRH administration was observed over the four trials. Reduction in the TSH response to TRH was not correlated with basal concentrations of thyroxine, triiodothyronine, or cortisol.     

The thyrotropin response to thyrotropin-releasing hormone as a biological marker of suicidal risk in depressive patients

In order to evaluate a possible predictive value for committing suicide of a reduced thyrotropin-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) stimulation we studied 306 depressed patients. The patients were followed for a mean of 5.8 (SD 2.9) years. During this period, 18 patients committed suicide. The TSH response to TRH stimulation in these 18 patients who committed suicide was lower than in the patients who did not commit suicide. The difference is not statistically significant. It is concluded that the TSH response to TRH cannot be said to identify the patients who later commit suicide.     

Human corticotropin-releasing hormone in depression--correlation with thyrotropin secretion following thyrotropin-releasing hormone

Twenty-two subjects (11 patients with major endogenous depression and 11 controls) received an intravenous test dose of 100 micrograms human corticotropin-releasing hormone (h-CRH). Corticotropin (ACTH), but not cortisol, responses were blunted in depressives. Basal cortisol secretion was higher in depressives than in controls and was negatively correlated to the corticotropin response following h-CRH. This finding indicates the integrity of the glucocorticoid-dependent negative feedback regulation in depression and supports the view that hypercortisolism in depression is primarily due to a suprapituitary disturbance. Comparison of ACTH responses after h-CRH with thyrotropin (TSH) output following thyrotropin-releasing hormone (TRH) revealed a positive correlation (r = 0.65, p less than 0.001). The concordance between ACTH and TSH responses after specific challenges suggests that regulation of both systems is at least in part under a common control.     

Cerebrospinal fluid amine metabolites in acute schizophrenia.

The metabolites of serotonin, dopamine, and norepinephrine, 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG), respectively, were studied in cerebrospinal fluid of patients with acute schizophrenia. Base line levels of these metabolites were not significantly different from those in normal, neurological, and affectively ill controls. Accumulations of 5HIAA and HVA following probenecid administration, which provide a measure of serotonin and dopamine turnover, were also not significantly different in patients with acute schizophrenia and affective illness. After patients had recovered from their acute schizophrenic illness, HVA accumulations were significantly reduced. We discuss results in relation to amine hypotheses of schizophrenia and the suggestion that altered dopamine metabolism may reflect a biological change predisposing to acute schizophrenia.     

Cerebrospinal fluid norepinephrine in affective illness

The authors measured cerebrospinal fluid norepinephrine concentrations in manic, depressive, and neurological control patients with and without probenecid administration. Baseline and probenecid norepinephrine values were significantly higher in manic than in depressed patients, who did not differ significantly from the neurological patients. Depressed patients with high levels of anxiety had higher levels of norepinephrine than those with low anxiety. These data suggest that alterations in mood or motor activity may be associated with changes in central norepinephrine metabolism in man.     

Biological predictors of treatment response in affective illness.

Attempts to identify biological response predictors generally have met with limited success, particularly where the goal is to develop clinically useful indices. This article reviews the biological approaches to predicting treatment response, beginning with neuroendocrine studies and electroencephalogram analysis and concluding with structural and functional neuroimaging. The article describes the designs of typical studies to aid in interpreting their results and concludes by addressing some of the problems and limitations associated with these approaches and suggesting future directions for this research.     

Comparison of growth hormone response after clonidine and insulin hypoglycemia in affective illness

Abnormal growth hormone (GH) responses have been observed after several neuroendocrine challenge tests. In the present study, we examined the relationship between GH response after clonidine and insulin administration within the same subject to see if consistent response patterns were evident. Though there was a significant reduction in the mean GH response after clonidine (p = 0.0002), similar differences were not observed after insulin (p = 0.10). Furthermore, there were no apparent within-subject correlations for GH response between the clonidine and insulin challenge tests. Although the present findings indicate an inherent variability in GH response patterns after different neuroendocrine challenge tests, it appears from prior studies that GH may be more consistently blunted after clonidine in depression when compared to other GH provocative tests.     

Dopaminergic effects of carbamazepine. Relationship to clinical response in affective illness

Carbamazepine, a drug used widely to treat epilepsy and trigeminal neuralgia, has been shown to be effective in the acute and prophylactic treatment of manic-depressive illness. While the time course of its antimanic effects parallels that of classic neuroleptics, indirect clinical evidence, such as lack of parkinsonian side effects and tardive dyskinesia, suggests that carbamazepine does not act by blocking dopamine receptors. To assess the effects of carbamazepine on dopamine mechanisms, we measured the dopamine metabolite homovanillic acid (HVA) in the cerebrospinal fluid of affectively ill patients before and after treatment. Carbamazepine did not alter basal concentrations of HVA, but decreased probenecid-induced accumulations of HVA, paralleling results in animal studies. In 25 patients, lower baseline cerebrospinal fluid HVA levels were related to subsequent better acute antidepressive responses to carbamazepine. While the precise mechanism of carbamazepine's effects on dopaminergic systems remains to be determined, this study provides further evidence that carbamazepine does not have a biochemical profile typical of neuroleptics.